IMPROVEMENTS IN OR RELATING TO CHIRAL AUXILIARIES

Abstract: Substantially entiomerically pure 3,3-disubstituted-5-monosubstituted pyrrolidin-2-ones of formula (I) in which R<2> is hydrogen and R and R<1> are as defined in the description, are useful chiral auxiliaries for the synthesis of chiral molecules. The 1-position nitrogen atom is a reactive centre to which may be reversibly coupled a wide range of groups containing prochiral centres, the substituent at the 5R- or 5S- position influencing the stereoselectivity of reactions performed on such groups. Compounds in which R<2> is an acyl group containing a prochiral centre are also claimed.

Description: "Improvements in or relating to chiral auxiliaries" This invention relates to new chiral auxiliaries and derivatives thereof useful in the synthesis of chiral molecules, in particular to new chiral auxiliaries containing a pyrrolidin-2-one ring structure. The use of chiral auxiliaries in the selective synthesis of single enantiomers of chiral molecules is now well known - see, for example, EP-A-0457469 and the references described therein. Such auxiliaries typically comprise (i) a reactive part carrying or to which may be coupled a moiety having a prochiral centre, and (ii) a chiral part which influences the stereochemical course of reactions at the prochiral centre, thereby encouraging the generation of substantially enantiomerically pure products. The auxiliary is preferably such that the desired single enantiomeric product can thereafter be uncoupled and recovered, with simultaneous regeneration of the reactive part of the auxiliary, thereby permitting a succession of subsequent sequences of coupling, stereoselective synthesis and uncoupling reaction stages using the same auxiliary. An important requirement of an auxiliary to be used in this way is that its basic structure should be substantially completely stable under the various reaction conditions employed, in particular that the structure should not be degraded under the conditions used for uncoupling of the desired stereoselective product. Similarly it is critical that uncoupling may be effected under conditions which are sufficiently mild not to induce racemisation of the desired substantially enantiomerically pure product. There is a need for auxiliaries with improved properties in respect of these requirements and which permit stereoselective syntheses involving a wide range of prochiral centre-containing moieties. The present invention is based on our finding that these objectives may be fulfilled by auxiliaries which are substantially enantiomerically pure 3,3- disubstituted-5-monosubstituted pyrrolidin-2-ones. Thus the l-position nitrogen atom in such compounds constitutes a reactive centre to which may be reversibly coupled a wide range of e.g. acyl groups containing prochiral centres. The substituent at the 5R- or 5S- position creates the chiral part of the auxiliary which will influence the stereoselectivity of reactions performed on substituent groups at the l-position. Such N-unsubstituted auxiliaries and their N- acylated derivatives are novel compounds and thus according to one aspect of the present invention there are provided compounds of general formula (I) (where the two R groups are identical lower alkyl groups or together form a lower alkylene group, R 1 represents an organic group and the asterisk denotes that R 1 is predominantly in the R- or S- configuration such that the compound (I) is in substantially enantiomerically pure form, and R 2 represents a hydrogen atom or an acyl group containing a prochiral centre) . The term substantially enantiomerically pure as used herein denotes compounds containing at least 80%, advantageously at least 90%, and preferably at least 95% of the desired enantiomer. Where the groups R in formula (I) represent lower alkyl groups these may, for example, contain 1-10, e.g. 1-6 carbon atoms, as in methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butvl and tert-butvl groups. When the R groups together represent a lower alkylene group this may, for example, contain 3-10 carbon atoms, e.g. as in trimethylene, tetramethylene, pentamethylene and hexamethylene groups. In a preferred class of compounds according to the invention both R groups represent methyl. The group R can be selected from a wide range of organic groupings, including, for example, aliphatic, cycloaliphatic and araliphatic groups, e.g. containing up to 20 carbon atoms and optionally carrying one or more substituents. R 1 may thus, for example, represent a group selected from c,.,,, alkyl such as methyl or ethyl; C 2 . 10 alkenyl such as vinyl or propenyl; C 3 . 10 cycloalkyl - C,. 4 alkyl such as cyclopentyl ethyl; C 6 . 12 aryl - C,_ 4 alkyl such as benzyl; and substituted versions of any of the preceding groups. One preferred category of R 1 groups may be represented by the formula - CH 2 0P (where P represents an organic group, e.g. as defined above for R 1 , especially a hydroxyl protecting group or a polymeric group) . Representative hydroxyl protecting groups include etherifying groups such as aralkyl (e.g. arylmethyl such as benzyl, p-nitrobenzyl or trityl) or hydrocarbylsilyl (e.g. trialkylsilyl such as trimethylsilyl or t- butyldi ethylsilyl) and esterifying groups, for example acyl groups such as alkanoyl (e.g. acetyl or pivaloyl) , alkenoyl (e.g. allylcarbonyl) , aroyl (e.g. p- nitrobenzoyl) , alkoxycarbonyl (e.g. t-butoxycarbonyl) , haloalkoxycarbonyl (e.g. 2,2,2-trichloroethoxycarbonyl) , aralkoxycarbonyl (e.g. benzyloxycarbonyl or p- nitrobenzyloxycarbonyl) or alkenyloxycarbonyl (e.g. allyloxycarbonyl) . Where P represents a polymer this may, for example, be an insoluble polymer, for example a crosslinked polysaccharide (e.g. a crosslinked agarose such as cepharose or a crosslinked dextran such as cephadex) or, more preferably, a divinylbenzene-crosslinked polystyrene system such as Merrifield's resin. The use of such insolubilised polymers, e.g. in bead form, as support systems for reagents is well known in the art. The first stage in the use of compounds of formula (I) in which R 2 represents a hydrogen atom as chiral auxiliaries will normally comprise the introduction of a prochiral centre-containing substituent at the 1- position of the pyrrolidine ring. Most commonly this substituent will be an acyl group, which may be represented by the formula - CO.R 2a where R 2a is an organic group, e.g. which is a prochiral precursor for a desired chiral moiety. Such groups may be introduced by, for example, reaction of a compound (I) in which R 2 represents a hydrogen atom with an acylating agent of formula (II) X.CO.R 2a (II) where R 2a is as defined above and X represents a leaving group, e.g. a halogen atom such as chlorine or bromine. Reaction of acyl halides of formula (II) is preferably carried out in the presence of a strong base, e.g. a metal alkyl such as n-butyl lithium. Such acylated compounds of formula (I) may be represented by formula (III) 0 (where R, R 1 , R 2a and the significance of the asterisk are as hereinbefore defined) . A wide range of R 2a groups may be present in the compounds of formula (III) , for example aliphatic, cycloaliphatic, araliphatic and aromatic groups, e.g. alkyl and alkenyl groups containing up to 10 carbon atoms such as ethyl, propyl or propenyl, C 6 . 10 aryl - C 4 alkyl groups such as benzyl or phenethyl, and C 6 _ 20 aryl groups such as phenyl or biphenyl groups. A variety of highly stereoselective reactions may be carried out on such compounds of formula (III) , depending on factors such as the nature and position of the prochiral centre in the chosen R 2a group. Such reactions constitute a further feature of the invention. In an important sub-class of compounds of formula (III) the R 2a group contains a terminal methylene group attached to the carbonyl group, so that the N- substituent may be written as - CO.CH 2 R 3 where R .CH-, corresponds to a group R 2a as hereinbefore defined. Such methylene groups constitute prochiral centres at which it is possible to effect asymmetric substitution with a high degree of stereoselectivity, e.g. by reaction with an electrophile. Where the substituent introduced by such an electrophilic substitution is represented by R (R 4 being an organic group) the stereochemistry of the substitution will predominantly (e.g. to an extent of about 90% or more) follow the pattern ( I V i ) ( V i ) or ( I V b ) ( V b ) (where R, R 1 , R 3 and R have the above-defined meanings). Sources of electrophiles which may be used in such reactions include, for example, alkyl and aralkyl halides, epoxides, aldehydes and ketones. The starting compound (IVa) or (IVb) is preferably reacted with a strong base capable of promoting enolisation of the side chain -CO.CH 2 - group (e.g. a Group IA, IIA or IIIA metal alkyl, metal alkyl halide or metal alkyl trifluoroacetate) , either during or, more preferably, before reaction with the source of electrophile. The reactions with the base and electrophile are preferably carried out in an inert solvent, e.g. a cyclic ether such as tetrahydrofuran, at a temperature of 0"C or less, if desired under an inert atmosphere, e.g. of nitrogen. Compounds of formula (III) in which R 2a represents a 1-alkenyl group, by virtue of being α,3-unsaturated ketones, may be subjected to Michael addition by reaction with a wide range of nucleophiles, e.g. malonic esters, acetoacetic esters, amines and derivatised amides, Grignard reagents etc., leading, where the 2- position of the alkenyl group is prochiral, to formation of substantially enantiomerically pure products. Such reactions are preferably carried out in an inert solvent at a temperature of 0°C or less, if desired under an inert atmosphere, and preferably in the presence of a base such as an alkali metal alkoxide or a tertiary amine. Compounds of formula (III) in which R 2a represents a 1-alkenyl group may also be subjected to stereoselective Diels-Alder reactions with appropriate conjugated dienes such as 1,3-butadiene, e.g. using thermal or Lewis acid catalysis. Compounds of formula (III) in which the α-carbon atom of the group R 2a carries a hydrogen atom may be subjected to stereoselective aldol condensations with aldehydes. Such reactions are preferably carried out at a temperature of 0 β C or less, e.g. -78'C, in an appropriate solvent and in the presence of a strong base serving to enolise the compound (III) , e.g. lithium diisopropylamide. The stereoselectivity of the reaction may be particularly enhanced by the use of boron enolates, e.g. generated from dibutylboronyl trifluoromethanesulphonate and diisopropylethylamine. Compounds of formula (III) in which R 2a is an aryl group may be subjected to a variety of stereoselective reactions in accordance with the invention. Thus, for example, a compound (III) in which R 2a is a substituted phenyl group may be subjected to a Birch reduction to yield a compound in which R 2a is a corresponding 2,5- cyclohexadienyl group, yielding this product in substantially enantiomerically pure form when the ring substitution pattern is such that a chiral centre is created at the l-position of the cyclohexadienyl group. The invention may also be useful in the synthesis of individual atropisomers of e.g. compounds in which R 2a is an appropriately substituted biphenyl group. After completion of the desired stereoselective asymmetric synthesis or syntheses the resulting product may be reacted to cleave the exocyclic nitrogen-carbon bond in order to release the desired product containing the newly created chiral centre and to regenerate an auxiliary of formula (I) in which R z represents a hydrogen atom. Such cleavage may be effected by, for example, acid or base catalysed hydrolysis, e.g. using an alkali metal hydroxide such as lithium hydroxide in an aqueous/organic solvent system such as aqueous tetrahydrofuran, to yield a carboxylic acid or carboxylate salt corresponding to the chiral side chain and carbonyl group. Oxidative cleavage, e.g. with hydrogen peroxide, may similarly give a carboxylic acid. Hydrolytic cleavage using bases such as alkali metal alkoxides or aralkoxides (e.g. lithium methoxide or benzoxide) or alkoxylated Grignard reagents (e.g. methoxy magnesium bromide) may be used to give corresponding alkyl or aralkyl carboxylate esters. Reductive cleavage, e.g. using a metal hydride reducing agent such as lithium aluminium hydride, may also be employed, yielding an alcohol grouping in place of the carbonyl group. The regenerated chiral auxiliary of formula (I) in which R 2 represents a hydrogen atom may be recovered, reacylated, e.g. by reaction with a compound of formula (II) as hereinbefore described, and used in further asymmetric syntheses. It will be appreciated that such recovery and reprocessing of an auxiliary according to the invention are rendered particularly easy where the auxiliary is attached to a polymer support, e.g. where R 1 in formula (I) is a group - CH 2 OP where P represents a polymer, preferably an insoluble polymer support system. The chiral auxiliaries of the invention may be prepared by any convenient method. Thus, for example, a substantially enantiomerically pure carboxyl-protected glutamic acid derivative having the formula (VI) COOR 5 H 2 N . CH . CH 2 . CH-.COOH (VI ) (where R 5 is a carboxyl protecting group, e.g. a lower alkyl group such as methyl or ethyl, and the significance of the asterisk is as hereinbefore defined) may be cyclised, e.g. in known manner, to yield a compound of formula (VII) (where R 5 and the asterisk have the above-defined meanings) . This compound may be reduced, e.g. using lithium aluminium hydride, to yield a corresponding 5R- or 5S-hydroxymethyl derivative which may, for example, be reacted with 2-methoxypropene to yield an isopropylidene derivative of formula (VIII) The compound (VIII) may be alkylated, e.g. in. two stages each comprising reaction with a strong base such as lithium diisopropylamide which is capable of promoting enolisation and with an alkyl halide R.Hal, or by similar reaction with a dihalide Hal.R.R.Hal to introduce an alkylene group, yielding after removal of the isopropylidene protecting group (e.g. by alcoholysis) a compound of formula (IX) (where R and the asterisk have the above-defined meanings) . Such a compound (IX) may, for example, be reacted with an appropriate etherifying or esterifying agent to yield a compound of formula (I) in which R 1 is a group ■ CH 2 OP where P is an etherifying or esterifying hydroxyl protecting group. Thus, for example, a compound (IX) may be reacted with t-butyldimethylsilyl chloride, e.g. in a solvent such as N,N-dimethylformamide, to introduce the protecting group t-butyldimethylsilyl or with trityl chloride, e.g. in a solvent such as methylene chloride in the presence of 4-dimethylaminopyridine and triethylamine, to introduce the protecting group trityl. Compounds of formula (IX) may be reacted with appropriately activated polymer systems, for example with a chloromethylated divinylbenzene-crosslinked polystyrene such as Merrifield's polymer, e.g. in the presence of base and a catalytic amount of a crown ether, to yield compounds of formula (I) in which R 1 is a group - CH 2 OP where P is a polymeric group. The hydroxyl group in the 5-substituent of compounds of formula (IX) may be converted to a leaving group, e.g. by tosylation. The product so obtained may be reduced, e.g. using sodium borohydride, to yield a compound (I) in which R 1 is methyl. Alternatively the product may be reacted with a diorganocopper lithium compound of formula (R 6 ) 2 CuL (where R 6 represents an organic group) to yield a compound (I) in which R 1 is a group of formula - CH 2 R 6 (where R 6 is as defined above) ; thus, for example, reaction with dimethylcopper lithium yields a compound (I) in which R 1 is an ethyl group. It will be appreciated that chiral auxiliaries according to the invention may also be prepared from N- protected derivatives of the carboxyl protected glutamate of formula (VI) . The N-protecting group may, for example, be removed at the end of the synthesis or may be a group R 2a .CO- (where R 2a is as defined above) . In synthesising the chiral auxiliaries of the invention one may in general start with appropriately protected derivatives of either D- or L-glutamic acid. It may be preferable to use derivatives of the naturally occurring L-glutamic acid, which has the formula (Via) COOH H 2 N. CH. CH 2 . CH 2 . COOH (Vi a) thereby leading to formation of compounds of formula (la) 0 (where R, R 1 and R 2 have the above meanings) . These enantiomers constitute a preferred feature of the invention. The following non-limitative examples serve to illustrate the invention. Example 1 f 5S) - f+) -l-Aza-2 . 2-dimethyl-3-oxa-8-oxobicyclo r 3 . 3 . 0 ~| - octane (2 ) ( 1 ) ( 2 ) The alcohol (1) (5.468g, 47.6 mmol) and a catalytic amount of pyridinium p-toluenesulphonate (PPTS) were dissolved in dry toluene (200 ml) . 2-Methoxypropene (36.4 ml, 380 mmol) was added dropwise and the mixture was heated under reflux overnight. After cooling to room temperature, the solvent was removed in vacuo and the crude residue was purified by flash chromatography, eluting with diethyl ether to give (2) as a white crystalline solid (6.52g, 89%), recrystallised in 40-60 petroleum ether; mp 38'C; maχ (CH 2 C1 2 ) : 1690 cm "1 ; [α] D 25 = +114.7° (c 1.0, CHC1 3 ) ; (Found: C, 61.55; H, 8.75; N, 8.77. C 8 H 13 N0 2 requires C, 61.91; H, 8.33; N, 9.03%); <S H (CDC1 3 , 200 MHz): 1.47 (3H, s, CH 3 ) , 1.67 (3H, s, CH 3 ) , 1.63-1.80 (IH, m, CHCH 2 ) , 2.04-2.18 (IH, m, CHCH 2 ) , 2.45 (IH, ddd, J=1.3, 9.1 and 16.6 Hz, C0CH 2 ) , 2.74 (IH, ddd, J=8.4, 12.3 and 16.6 Hz, C0CH 2 ) , 3.38 (IH, t, J=9.0 Hz, OCH 2 ) , 4.01 (IH, dd, J=5.7 and 9.0 Hz, OCH 2 ) , and 4.12- 4.27 (IH, m, CH) ; δ c (CDC1 3 , 50 MHz): 23.60 (CH 3 ) , 24.14 (CH 2 ) , 26 . 64 ( CH 3 ) , 37 . 06 (CH-,) , 61 . 54 ( CH) , 69 . 85 ( CH.,) , 91.26 (C) , and 171.69 (CO); m/z (CI + , NH 3 ) : 156 (M + +l) . Example 2 (5S)-(+)-l-Aza-3-oxa-8-oxo-2.2.7.7-tetramethyl- bicvclor3.3.01-octane (3) ( 3 ) To a solution of the protected alcohol (2) from Example 1 (3.93g, 25.4 mmol) dissolved in dry tetrahydrofuran (THF) (90 ml) and cooled to -78*C was added a solution of lithium diisopropylamide (LDA) (0.5M, 60.86 ml, 30.5 mmol) in THF. This mixture was stirred for 30 minutes. Methyl iodide (1.91 ml, 30.48 mmol) was then added and the mixture was allowed to reach room temperature. The mixture was cooled again to -78*C and another solution of LDA (0.5M, 65.9 ml, 33 mmol) in THF was added. After one hour of stirring methyl iodide (2.1 ml, 33.5 mmol) was added and the mixture was stirred for 20 minutes at -78 β C, warmed up to room temperature and left overnight. Reaction was quenched by addition of brine (15 ml) and the resulting mixture was extracted with diethyl ether and dried (MgS0 4 ) . After concentration in vacuo the crude residue was purified by flash column chromatography, eluting with ethyl acetate/40-60 petroleum ether (1:3) to give (3) as a white crystalline solid (4.0g, 86%); p 74-75°C; mχ (CH 2 C1 2 ) : 1686 cm "1 ; [α] Q 25 = +71.2° (c 1.0, CHC1 3 ) ; (Found: C, 65.47; H, 9.44; N, 7.32. C 10 H 17 NO 2 requires C, 65.54; H, 9.35; N, 7.64%); δ H (CDC1 3 , 200 MHz): 1.16 (3H, s, gem -CH 3 ) , 1.2 (3H, s, gem -CH 3 ) , 1.44 (3H, s, CH 3 ) , 1.58 (IH, dd, J=8.6 and 12.1 Hz, CHCH 2 ) , 1.63 (3H, s, CH 3 ) , 2.00 (IH, dd, J=5.7 and 12.1 HZ, CHCH 2 ) , 3.33-3.48 (IH, m, OCH 2 ) , and 4.05- 4.23 (2H, , NCH and OCH 2 ) ; <S C (CDC1 3 , 50 MHz): 23.69 (CH 3 ) , 24.21 (CH 3 ) , 25.04 (CH 3 ) , 26.57 (CH 3 ) , 39.68 (CH 2 ) , 47.65 (C) , 57.33 (CH) , 70.20 (CH 2 ) , 91.22 (C) , and 176.50 (CO) ; m/z (CI + , NH 3 ) : 184 (M * +l) . Example 3 (5S)-f+)-3.3-Dimethyl-5-hvdroxymethylpyrrolidin-2-one 111 0 Ϊ— O H ( 4) A solution of the oxazolidinone (3) from Example 2 (0.8g, 4.37 mmol) and p-toluenesulphonic acid (PTSA) (O.Olg) in dry methanol (50 ml) was refluxed for 90 minutes. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified by flash column chromatography, eluting with ethyl acetate/ methanol (9:1) to give (4) as a white solid (0.598g, 96%), recrystallised in diethyl ether; mp 38-39'C; i/^ (CH 2 C1 2 ) : 3289 and 1685 cm "1 ; [α]„ 25 = +80.5° (c 1.0, CHC1 3 ) ; (Found: C, 58.59; H, 9.13; N, 9.41. C 7 H 13 N0 2 requires C, 58.72; H, 9.15; N, 9.70%); <S„ (CDC1 3 , 200 MHz): 1.15 (6H, s, gem -CH 3 ) , 1.56 (IH, dd, J=8.1 and 12.7 Hz, CCH 2 ) , 1.95 (IH, dd, J=7.1 and 12.7 Hz, CCH 2 ) , 3.36-3.45 (IH, m) , 3.65-3.77 (2H, m) , 5.06 (IH, br-s, OH), and 7.63 (IH, br-s, NH) ; <5 C (CDC1 3 , 50 MHz): 24.79 (CH 3 ) , 24.92 (CH 3 ) , 38.07 (CH 2 ) , 40.34 (C) , 53.18 (CH) , 65.70 (CH 2 ) , and 183.74 (CO); m/z (CI*, NH 3 ) : 144 (M*+l) Example 4 f5S>- (+)-5-t-Butyldimethylsilyloxymethyl-3.3- dimethylpyrrolidin-2-one ( 4 ) ( 5 ) The alcohol (4) from Example 3 (0.582g, 4.07 mmol) was dissolved in N,N-dimethylformamide (DMF) (4 ml). Imidazole (0.291g, 4.27 mmol) and t-butyldimethylsilyl chloride (0.644g, 4.27 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was poured onto water (10 ml) and extracted with ether. The combined extracts were washed with brine and dried (MgS0 4 ) . After concentration in vacuo the residue was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1:1) to give (5) as a white solid (0.798g, 76%); mp 94"C; ι |naχ (CH 2 C1 2 ) : 1700 cm '1 ; [α] D 22 - 5 = +46.8° (c 1.0, CHC1 3 ) ; (Found: C, 60.85; H, 10.73; N, 5.29. C 13 H 27 N0 2 Si requires C, 60.65; H, 10.57; N, 5.44%); <S H (CDC1 3 , 200 MHz): 0.07 (6H, Ξ, Si(CH 3 ) 2 , 0.9 (9H, s, SiC(CH 3 ) 3 ), 1.20 (6H, s, C(CH 3 ) 2 ), 1.52 (IH, dd, J=7.8 and 9.8 Hz, CCH 2 ) , 1.98 (IH, dd, J=6.8 and 9.8 Hz, CCH 2 ) , 3.38 (IH, dd, J=6.4 and 8.3 Hz, OCH 2 ) , 3.61-3.77 (2H, m, OCH 2 and CH) , and 5.94 (IH, s, NH) ; δ. (CDCl 3 , 50 MHZ): -5.63 (CH 3 ) , 18.06 (C) , 25.12 (CH 3 ) , 25.30 (CH 3 ) , 25.70 (CH 3 ) , 38.33 (CH 2 ) , 52.42 (CH) , 67.32 (CH 2 ) , and 182 (CO); m/z (CI + , NH 3 ) : 258 (M + +l) . Example 5 f5S)-(+)-3.3-Dimethyl-5-triphenylmethoxymethyl- pyrrolidin-2-one (6) 0 ' ^ O C P 3 ( 6 ) The alcohol (4) from Example 3 (0.5g, 3.5 mmol) was dissolved in dichloromethane (4 ml) . To this solution were added 4-dimethylaminopyridine (DMAP) (catalytic amount), triethylamine (1 ml, 7 mmol), and triphenylmethyl chloride (1.07g, 3.68 mmol). The resulting mixture was stirred at room temperature overnight and then poured onto saturated aqueous sodium bicarbonate solution. The mixture was repeatedly extracted with dichloromethane and the combined extracts were washed with brine and dried (MgS0 4 ) . After concentration in vacuo the residue was purified by flash column chromatography, eluting with ethyl acetate/40-60 petroleum ether (1:1) to give (6) as a white solid (0.954g, 71%), recrystallised in ethyl acetate; mp 187 * C; i/^ (nujol) : 1685 cm "1 ; [α] 0 24 = +10.6° (c 0.5, CHC1 3 ) ; (Found: C, 81.12; H, 7.23; N, 3.50. C 26 H 22 N0 2 requires C, 81.01; H, 7.06; N, 3.63%); 6 H (CDC1 3 , 200 MHZ): 1.12 (3H, s, CH 3 ) , 1.19 (3H, s, CH 3 ) , 1.47 (IH, dd, J=8.2 and 12.7 Hz, C(CH 3 ) 2 CH 2 ) , 1.95 (IH, dd, J=7.1 and 12.7 Hz, C(CH 3 ) 2 CH 2 ), 3.01 and 3.21 (2H, ddd, J=3.9, 8.7 and 9.0 Hz), 3.79-3.93 (IH, , CH) , 6.45 (IH, br-s, NH) , and 7.07-7.48 (15H, m, aryl); <S C (CDC1-., 50 MHz): 24.97 (CH 3 ) , 25.19 (CH 3 ) , 38.90 (CH-.) , 39.97 (C) , 50.65 (CH) , 67.60 (CH 2 ) , 86.85 (C) , 127.39 (CH) , 128.12 (CH) , 128.78 (CH) , 143.85 (C) , and 182.69 (CO); m/z (CI + , NH 3 ) : 386 (M * +l) . Example 6 (5S)- (+)-3.3-Dimethyl-5-p-toluenesulphonyloxγmethyl- pyrrolidin-2-one (7) 0 θ ~~ s ( 7 ) To the alcohol (4) from Example 3 (0.143g, 1 mmol) dissolved in dichloromethane (15 ml) and pyridine (2 ml) was added p-toluenesulphonyl chloride (0.285g, 1.5 mmol) . The resulting mixture was stirred overnight at room temperature. Hydrochloric acid solution (0.5M, 50 ml) was added, the product was extracted with dichloro¬ methane (3x30 ml) and the combined extracts were dried over MgS0 4 . After concentration of the organic phase in vacuo the residue was purified by flash column chromatography, eluting with ethyl acetate/methanol (9:1) to give (7) as a crystalline solid (0.273g, 92%); mp 116-117°C; ^ (CH 2 C1 2 ) : 1713 cm "1 ; [α] D 25 = +20° (c 0.5, CHC1 3 ) ; (Found: C, 56.39; H, 6.66; N, 4.56. C 14 H 19 SN0 4 requires C, 56.55; H, 6.44; N, 4.71%); δ H (CDC1 3 , 200 MHz): 1.15 (6H, s, C(CH 3 ) 2 ), 1.54 (IH, dd, J=7.4 and 12.9 Hz, CCH 2 ) , 2.04 (IH, dd, J=6.7 and 13.0 Hz, CCH 2 ) , 3.78- 3.91 (2H, m) 4.06-4.09 (IH, m) , 6.11 (IH, br-s, NH) , 7.34 (2H, d, J=8.2 Hz, aryl H) , 7.8 (2H, d, J=8.2 Hz, aryl); <5 C (CDC1 3 , 50 MHz): 21.00 (aryl-CH 3 ) , 25.05 (C(CH 3 ) 2 ), 38.16 (CH 2 ) , 39.90 (C(CH 3 ) 2 ), 49.44 (CH) , 72.30 (CH 2 ) , 128.12 (CH) , 130.24 (CH) , 132.55 (C) , 143.56 (C) , and 182.83 (CO); m/z (CI + , NH 3 ) : 298 (M * +l) . Example 7 (5R)-(-)-3.3-Dimethyl-5-ethylpyrrolidin-2-one (8) ( 8 ) A solution of Me 2 CuLi in THF was prepared at -20*C by slow addition of a methyl lithium solution (1.4M in hexane, 25.4 ml, 35.4 mmol) to copper iodide (3.36g, 17.7 mmol) in THF (20 ml) . To this solution was then added a solution of (7) from Example 6 (1.75g, 5.9 mmol) in THF (20 ml) . After 45 minutes at this temperature the mixture was stirred at 0°C overnight and then quenched by addition of saturated aqueous ammonium chloride solution (50 ml) . The product was extracted with diethyl ether (3x40 ml) and the combined extracts were washed with brine and dried (MgS0 4 ) . Concentration in vacuo left a brown solid which was filtered on a small column of silica, eluting with ethyl acetate to give (8) as a white solid (0.756g, 91%); ι Mχ (CH 2 C1 2 ) : 1698 cm '1 ; [α] D 22 = -28° (c 2.0, CHC1 3 ) ; (Found: C, 67.97; H, 11.28; N, 9.46. C 8 H 15 N0 requires C, 68.04; H, 10.71; N, 9.92%); <5 H (CDC1 3 , 300 MHz): 0.92 (3H, t, J=7.4 Hz, CH 2 CH 3 ) , 1.16 (3H, s, (CH 3 ) 2 ), 1.18 (3H, Ξ, (CH 3 ) 2 ), 1.53 (3H, m, CH 2 CH 3 + IH, CH 2 CH) , 2.06 (IH, dd, J=6.7 and 12.6 Hz, CH 2 CH) , 3.50 (IH, CHCH 2 CH 3 ) , 6.01 (IH, br-s, NH) ; m/z (CI + , NH 3 ) : 142 (M * +l) . Example 8 (5R) - (- . -3 . 3 .5-Trimethylpyrrolidin-2-one (9) ( 9 ) In a schlenck tube under argon were placed compound (7) from Example 6 (2.55g, 8.58 mmol), sodium borohydride (0.715g, 18.9 mmol) and freshly distilled dimethyl- sulphoxide (DMSO) (25 ml) . This mixture was heated at 85'C for 2.5 hours and then cooled to room temperature. Water (20 ml) was added and then brine (30 ml) . The product was extracted with dichloromethane (5x40 ml) and the combined extracts were dried (MgS0 4 ) . After concentration in vacuo the residue was purified by flash column chromatography, eluting with ethyl acetate to give (9) as a white solid (l.OOg, 92%); ι (naχ (CH 2 C1 2 ) : 1700 cm '1 ; [α] D 22 = -22.5° (c 2.0, CHCl 3 ) ; (Found: C, 66.07; H, 10.23; N, 10.81. C 7 H 13 NO requires C, 66.10; H, 10.30; N, 10.93%); (S H (CDC1 3 , 300 MHz): 1.16 (3H, s, (CH 3 ) 2 ), 1.19 (3H, s, (CH 3 ) 2 ), 1.22 (3H, d, J=6.2 Hz, CH 3 CH) , 1.52 (IH, dd, J=8.2 and 12.6 Hz, CH 2 CH) , 2.09 (IH, dd, J=6.5 and 12.6 Hz, CH 2 CH) , 3.71 (IH, m, CH) , 6.00 (IH, br-s, NH) ; m/z (CI + , NH 3 ) : 128 (M + +l) . Examples 9-23 General procedure for N-acylation The N-unsubstituted auxiliary was dissolved in THF and cooled to -78*C. nBuLi in hexane was then added dropwise and the mixture stirred at -78*C for 1 hour. Freshly distilled acid chloride was added and the mixture was allowed to reach room temperature. The reaction mixture was then poured onto water and the product was extracted with diethyl ether. The combined extracts were washed with brine and dried (MgS0 4 ) . After concentration in vacuo the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/40-60 petroleum ether to give the N-acylated auxiliary. Example 9 (5Sϊ- (+)-5-t-Butyldimethylsilyloxymethyl-3.3-dimethyl-l- propionylpyrrolidin-2-one flO) 2 1 B u ( 1 0 ) Reaction of the auxiliary (5) from Example 4 (0.147g, 0.572 mmol) in solution in THF (5 ml) with nBuLi (1.4M, 0.41 ml, 0.572 mmol) and propionyl chloride (0.075 ml, 0.86 mmol) furnished the N-acyl derivative (10) as a colourless oil (0.146g, 82%); v^ (thin film): 1698 and 1739 cm "1 ; [α] D 26 - 5 = +54° (c 1.15, CHC1 3 ) ; (Found: C, 61.57; H, 10.25; N, 64.55. C, 6 H 31 N0 2 Si requires C, 61.30; H, 9.97; N, 4.47%) ; δ H (CDC1 3 , 200 MHz) : -0.03 (3H, s, SiCH 3 ) , -0.08 (3H, Ξ, SiCH 3 ) , 0.83 (9H, s, SiC(CH 3 ) 3 , 1.10 (3H, t, J=7.3 Hz, CH 3 ) , 1.16 (3H, s, CCH 3 ) , 1.24 (3H, s, CCH 3 ) , 1.84-2.04 (2H, m, CCH 2 ) , 2.87 (IH, q, J=10.7 Hz, C0CH 2 ) , 2.88 (IH, q, J=7.4 Hz, C0CH 2 ) , 3.63 (IH, dd, J=2.4 and 10.2 Hz, 0CH 2 ) , 3.94 (IH, dd, J=4.8 and 10.2 Hz, OCH 2 ) 4.16-4.27 (IH, m, CHN) , δ- (CDC1 3 , 50 MHz) : - 5.71 (CH 3 ) , 8.17 (CH 3 ) , 18.06 (C) , 25.46 (CH 3 ) , 25.66 (CH 3 ) , 27.31 (CH 3 ) , 30.73 (CH 2 ) , 34.59 (CH 2 ) , 41.54 (C) , 54.64 (CH) , 62.40 (CH 2 ) , 176.14 (CO), 181.81 (CO) ; m/z (CI + , NH 3 ) : 314 (M*+l) . Example 10 (5S)-(-)-5-t-Butyldimethylsilyloxymethyl-3.3-dimethyl-l- pivaloylpyrrolidin-2-one fll) ( 1 1 ) Reaction of the auxiliary (5) from Example 4 (0.050g, 0.195 mmol) in solution in THF (3 ml) with nBuLi (1.4M, 0.14 ml, 0.195 mmol) and pivaloyl chloride (0.036 ml) furnished the N-acyl derivative (11) as a clear oil (0.046g, 70%) ; ^ (thin film): 1739 and 1687 cm "1 ; [α] D o - 5 = -41° (c 0.83, CHC1 3 ) ; <5 H (CDC1 3 , 200 MHz) : 0.00 (3H, Ξ, SiCH 3 ) , 0.02 (3H, s, SiCH 3 ) , 0.86 (9H, s, Si(CH 3 ) 3 ) , 1.16 (3H, s, C(CH 3 ) 2 ) , 1.24 (3H, Ξ, C(CH 3 ) 2 ), 1.31 (9H, s, C0C(CH 3 ) 3 ) , 1.88 (IH, dd, J=8.3 and 12.8 Hz, CCH 2 ) , 1.98 (IH, dd, J=7.0 and 12.8 Hz, CCH 2 ) , 3.52 (IH, dd, J=2.3 and 10.4 Hz, OCH 2 ) 3.87 (IH, dd, J=2.3 and 10.4 Hz, 0CH 2 ) , 4.18-4.28 (IH, m, CH) ; <S C (CDC1 3 , 50 MHz) : - 5.74 (CH 3 ) , 18.13 (C) , 25.50 (CH 3 ) , 25.72 (CH 3 ) , 26.36 (CH 3 ) , 34.75 (CH 2 ) , 41.50 (C) , 42.16 (C) , 55.95 (CH) , 62.08 (CH 2 ) , 182.76 (CO) ; m/z (Cl\ NH 3 ) : 342 (M*+l) . Example 11 (5S>-(-)-5-t-Butyldimethylsilyloxymethyl-3.3-dimethyl-l- (3-phenylpropionyl)pyrrolidin-2-one (12) ( 12) Reaction of the auxiliary (5) from Example 4 (0.183g, 0.71 mmol) in solution in THF (10 ml) with nBuLi (1.4M, 0.51 ml, 0.712 mmol) and 3-phenylpropionyl chloride (0.16 ml, 1.07 mmol) furnished the N-acyl derivative (12) as a colourless oil (0.196g, 71%) ; v maχ (thin film): 1737, 1695, 1605 and 837 cm "1 ; [α] D 26 ' 5 = -109° (c 0.28, CHC1 3 ) ; δ H (CDC1 3 , 200 MHz): 0.01 (3H, s, SiCH 3 ) , 0.04 (3H, s, SiCH 3 ) , 0.88 (9H, s, SiC(CH 3 ) 3 ) , 1.93 (2H, m, CHCH 2 ) , 2.96 (2H, t, J=7.81 Hz, COCH 2 ) , 3.16-3.29 (2H, m, CH 2 Ph) , 3.66 (IH, dd, J=2.3 and 10.1 Hz, OCH 2 ) , 3.98 (IH, dd, J=4.8 and 10.1 Hz, OCH 2 ) , 4.20-4.31 (IH, m, CH) , 7.11-7.33 (5H, m, aryl) ; <S C (CDC1 3 , 50 MHz): -5.69 (CH 3 ) , 18.13 (C) , 25.52 (CH 3 ) , 25.74 (CH 3 ) , 25.66 (CH 3 ) , 27.38 (CH 3 ) , 30.36 (CH 2 ) , 34.59 (CH 2 ) , 38.95 (CH 2 ) , 41.61 (C) , 54.71 (CH) , 62.46 (CH 2 ) , 126.24 (CH) , 128.57 (CH) , 128.72 (CH) , 141.16 (C) , 174.49 (CO) , 181.88 (CO) ; m/z (CI + , NH 3 ) : 390 (M + +l) . Example 12 C5S) -(-)-3.3-Dimethyl-l-propionyl-5-triphenylmethoxy- methylpγrrolidin-2-one (13) ( 1 3 ) Reaction of the auxiliary (6) from Example 5 (0.25g, 0.65 mmol) in solution in THF (3 ml) with nBuLi (1.4M, 0.46 ml, 0.65 mmol) and propionyl chloride (0.085 ml, 0.98 mmol) furnished the N-acyl derivative (13) as a crystalline solid (0.238g, 83%) ; [α] 0 26 - 5 = -80° (c 0.5, CHCl j ) ; (Found: C, 78.83; H, 7.32; N, 2.99. C 28 H 23 N0 3 requires C, 78.52; H, 7.50; N, 3.16%) ; <S H (CDC1 3 , 200 MHz) : 1.17 (3H, t,J=7.4 Hz, CH 2 CH 3 ) , 1.19 (3H, s, CCH 3 ) , 1.21 (3H, s, CCH 3 ) , 1.93-2.08 (2H, m, CHCH 2 ) , 2.84-3.08 (2H, m, COCH 2 ) , 3.36 (IH, J=6.4 and 9.1 Hz, OCH 2 ) , 3.49 (IH, J=3.4 and 9.1 Hz, OCH 2 ) , 4.33-4.45 (IH, m, CH) , and 7.22-7.49 (15H, m, aryl) ; δ Q (CDC1 3 , 50 MHz) : 8.23 (CH 3 ) , 25.68 (CH 3 ) , 27.31 (CH 3 ) , 30.80 (CH 2 ) , 34.99 (CH 2 ) , 41.65 (C) , 53.21 (CH) , 63.11 (CH 2 ) , 86.73 (C) , 127.32 (CH) , 128.08 (CH) , 128.84 (CH) , 144.08 (C) , 175.93 (CO) , and 181.71 (CO) ; m/z (CI\ NH 3 ) : 442 (M * +l) . Example 13 (5S)-(-)-3,3-Dimethyl-l-pivaloyl-5-triphenylmethoxy- methylpyrrolidin-2-one (14) ' ^0C P h ( 1 4 ) Reaction of the auxiliary (6) from Example 5 (0.25g, 0.65 mmol) in solution in THF (3 ml) with nBuLi (1.4M, 0.46 ml, 0.65 mmol) and pivaloyl chloride (0.12 ml, 0.98 mmol) furnished the N-acylated derivative (14) as a white crystalline solid (0.263g, 86%) ; [α] 0 26-5 = -44* (c 0.5, CHC1 3 ) ; (Found: C, 79.09; H, 7.69; N, 2.78. C 31 H 35 N0 3 requires C, 79.29; H, 7.51; N, 2.98%) ; <S H (CDC1 3 , 200 MHz) : 1.20 (3H, s, CCH 3 ) , 1.24 (3H, s, CH 3 ) , 1.96 (IH, J=8.7 and 13.0 Hz, CCH 2 ) , 2.02 (IH, J=6.6 and 13.0 Hz, CCH 2 ) , 3.23 (IH, dd, J=5.1 and 9.4 Hz, 0CH 2 ) , 3.44 (IH, dd, J=3.7 and 9.4 Hz, OCH 2 ) , 4.34-4.44 (IH, m, CH) , 7.22- 7.47 (15H, , aryl) ; <S C (CDC1 3 , 50 MHz) : 25.63 (CH 3 ) , 25.89 (CH 3 ) , 26.38 (CH 3 ) , 26.67 (CH 3 ) , 35.31 (CH 2 ) , 41.65 (C) , 42.13 (C) , 54.68, 62.76 (CH 2 ) , 86.71 (C) , 127.32 (CH) , 128.05 (CH) , 128.87 (CH) , 143.96 (C) , 180.24 (CO) , and 182.25 (CO) . Example 14 t 5S) - (-) -l-Propionyl-3.3.5-trimethylPyrrolidin-2-one (15) ( 1 5 ) Reaction of the auxiliary (9) from Example 8 (0.710g, 5.6 mmol) in solution in THF (25 ml) with nBuLi (1.6M, 3.84 ml, 6.15 mmol) and propionyl chloride (0.58 ml, 6.7 mmol) furnished the N-acyl derivative (15) as a colourless oil (0.92g, 90%); i,^ (CH 2 C1 2 ) : 1696 and 1731 cm" 1 ; [α] D 23 = -101° (c 0.5, CHC1 3 ) ; (Found: C, 65.75; H, 9.04; N, 7.95. C 10 H 17 NO 2 requires C, 65.54; H, 9.35; N, 7.64%); <S H (CDC1 3 , 300 MHz) : 1.08 (3H, t, J=7.3 Hz, CH 2 CH 3 ) , 1.30 (3H, s, CH 3 ) 2 ), 1.24 (3H, s, (CH 3 ) 2 ), 1.34 (3H, d, J=6.3 Hz, CHCH 3 ) , 1.52 (IH, dd, J=5.4 and 13.0 Hz, CH 2 CH) , 2.08 (IH, dd, J=9.6 and 13.0 Hz, CH 2 CH) , 2.86 (2H, m, CH 2 CH 3 ) , 4.20 (IH, m, CHCH 3 ) ; m/z (CI * , NH 3 ) : 184 (M * +l) . Example 15 (5R)-(-)-l-Isovaleryl-3.3.5-trimethylpyrrolidin-2-one ( 1 6 ) Reaction of the auxiliary (9) from Example 8 (0.187g, 1.5 mmol) in solution in THF (15 ml) with nBuLi (1.6M, 1.03 ml, 1.65 mmol) and isovaleryl chloride (0.22 ml, 1.8 mmol) furnished the N-acyl derivative (16) as a colourless oil (0.232g, 75%) ; Vmω . (CH 2 C1 2 ) : 1692 and 1731 cm "1 ; [α]^ -78° (c 0.5, CHC1 3 ) ; (Found: C, 67.80; H, 10.29; N, 6.64. C 12 H 2l N0 2 requires C, 68.21; H, 10.02; N, 6.63%) ; <S H (CDC1 3 , 300 MHz) : 0.93 (3H, t, J=2.8 Hz, CH 3 CHCH 3 ) , 0.97 (3H, d, J=2.8 Hz, CH 3 CHCH 3 ) , 1.16 (3H, s, (CH 3 ) 2 ) , 1.26 (3H, s, (CH 3 ) 2 ) , 1.36 (3H, d, J=6.0 Hz , CH 3 CH) , 1.54 (IH, dd, J=5.6 and 13.0 Hz, CH 2 CH) , 2.11 (2H, , IH CH 2 CH+CH(CH 3 ) 2 ) , 2.68 (IH, dd, J=7.0 and 15.0 Hz, COCH 2 ) , 2.79 (IH, dd, J=6.3 and 15 Hz, COCH 2 ) , 4.25 (IH, m, NCH) ; m/z (CI + , NH 3 ) : 212 (M*+l) ; 196; 169; 128. Example 16 (5R)-(+)-l-Pivaloyl-3.3.5-trimethylpyrrolidin-2-one (17) 0 0 ( 1 7 ) Reaction of the auxiliary (9) from Example 8 (0.20g, 1.57 mmol) in solution in THF (20 ml) with nBuLi (1.6M, 1.08 ml, 1.73 mmol) and pivaloyl chloride (0.24 ml, 1.9 mmol) furnished the N-acyl derivative (17) as a colourless oil (0.293g, 88%); mχ (CH 2 C1 2 ) : 1687 and 1731 cm "1 ; [a] 0 a = +9° (c 0.5, CHC1 3 ) ; (Found: C, 68.40; H, 10.61; N, 6.42. C 12 H 21 N0 2 requires C, 68.21; H, 10.61; N, 6.63%); δ H (CDC1 3 , 300 MHz): 1.12 (3H, s, (CH 3 ) 2 ), 1.22 (3H, s, (CH 3 ) 2 ), 1.29 (9H, s, C(CH 3 ) 3 ), 1.53 (IH, dd, J=8.1 and 13.0 Hz, CH 2 CH) , 2.08 (IH, dd, J=8.0 and 13.0 HZ, CH 2 CH) , 4.22 (IH, m, NCH); m/z (Cl\ NH 3 ) : 212 (M*+l) ; 156; 128. Example 17 (5R)-(-)-l-(3-Phenylpropionyl)-3.3.5-trimethyl- pyrrolidin-2-one (18) ( 1 8 ) Reaction of the auxiliary (9) from Example 8 (0.40g, 3.15 mmol) in solution in THF (30 ml) with nBuLi (1.6M, 2.17 ml, 3.46 mmol) and 3-phenylpropionyl chloride (0.56 ml, 3.78 mmol) furnished the N-acyl derivative (18) as a colourless oil (0.743g, 91%); i,^ (CH 2 C1 2 ) : 1693 and 1731 cm "1 ; [o]^ -64° (c 0.5, CHC1 3 ) ; (Found: C, 74.41; H, 8.25; N, 4.95. C 16 H 21 N0 2 requires C, 74.09; H, 8.16; N, 5.40%); «S H (CDC1 3 , 300 MHz): 1.18 (3H, s, (CH 3 ) 2 ), 1.20 (3H, s, (CH 3 ) 2 ), 1.35 (3H, d, J=6.8 Hz, CH 3 CH) , 1.54 (IH, dd, J=5.3 and 13.1 Hz, CH 2 CH) , 2.08 (IH, dd, J=7.9 and 13.1 HZ, 2.95 (2H, t, J=8.0 Hz, CH 2 CH 2 ) , 3.24 (2H, t, J=8.0 HZ, CH 2 CH 2 ) , 4.24 (IH, m, NCH), 7.25 (5H, m, aryl); m/z (CI + , NH 3 ) : 260 (M + +l) , 128. Example 18 (5R)-(-)-1-Butyryl)-3.3.5-trimethylpyrrolidin-2-one (19) ( 1 9 ) Reaction of the auxiliary (9) from Example 8 (0.40g, 3.15 mmol) in solution in THF (15 ml) with nBuLi (1.6M, 2.16 ml, 3.46 mmol) and butyryl chloride (0.37 ml, 3.78 mmol) furnished the N-acyl derivative (19) as a colourless oil (0.583g, 94%); v mχ (CH 2 C1 2 ) : 2970, 1731 and 1694 cm '1 ; [α] D 1 = -90.7° (c 0.7, CHC1 3 ) ; (Found: C, 66.97; H, 9.88; N, 7.00. C H 19 N0 2 requires C, 66.97; H, 9.71; N, 7.10%); δ H (CDC1 3 , 300 MHz): 0.94 (3H, t, J=7.4 HZ), 1.15 (3H, s) , 1.25 (3H, s) , 1.34 (3H, d, J=6.4 Hz) , 1.54 (IH, dd, J=5.3 and 13.1 Hz), 1.63 (2H, m) , 2.08 (IH, dd, J=8.5 and 13.1 Hz), 2.84 (2H, dt, J=1.8 and 7.3 Hz), 4.23 (IH, m) ; m/Z (CI\ NH 3 ) : 198 (M + +l) , 128. Example 19 (5R)-(-)-l-Crotonyl-3.3.5-trimethylpyrrolidin-2-one (20) 0 0 ( 20) Reaction of the auxiliary (9) from Example 8 (0.59g, 4.65 mmol) in solution in THF (15 ml) with nBuLi (1.6M, 3.0 ml, 4.88 mmol) and crotonyl chloride (0.50 ml, 5.11 mmol) furnished the N-acyl derivative (20) as a colourless oil (0.837g, 92%); ι/ Mχ (CH 2 C1 2 ) : 2967, 1729, 1681, 1637 and 1337 cm '1 ; [α] D 24 = -114.5° (c 1.16, CHC1 3 ) ; (Found: C, 67.77; H, 8.80; N, 7.24. C n H 17 N0 2 requires C, 67.66; H, 8.77; N, 7.17%); <S H (CDC1 3 , 300 MHz): 1.18 (3H, S) , 1.28 (3H, s) , 1.35 (3H, d, J=6.3 Hz) , 1.57 (IH, dd, J=5.5 and 12.9 HZ), 1.93 (3H, d, J=6.4 Hz), 2.11 (IH, dd, J=8.23 and 12.9 Hz), 4.28 (IH, m) , 7.17 (2H, m) ; m/z (CI + , NH 3 ) : 197, 196 (M*+l) , 195, 180, 128, 69. Example 20 ( 5R) - ( -) -3 , 3-Dimethγl-5-ethyl-l-propionylpyrrol idin-2- one ( 21 ) ( 2 1 ) Reaction of the auxiliary (8) from Example 7 (0.756g, 5.36 mmol) in solution in THF (15 ml) with nBuLi (1.6M, 3.69 ml, 5.90 mmol) and propionyl chloride (0.56 ml, 6.43 mmol) furnished the N-acyl derivative (21) as a colourless oil (0.924g, 87%); v mχ (CH 2 C1 2 ) : 1732 and 1696 cm "1 ; [α] D 21 = -121.2* (c 0.8, CHC1 3 ) ; (Found: C, 67.25; H, 9.91; N, 6.67. C^H^NO j requires C, 66.97; H, 9.71; N, 7.10%); <S H (CDC1 3 , 300 MHz): 0.87 (3H, t, J=7.5 Hz) , 1.13 (3H, t, J=7.5 Hz), 1.17 (3H, s) , 1.26 (3H, s) , 1.42 (IH, m) , 1.65 (IH, dd, J=5.4 and 13.2 Hz), 2.01 (2H, d, J=8.7 and 13.2 Hz), 2.06 (IH, m) , 2.90 2H, m) , 4.05 (IH, m) ; m/z (CI\ NH 3 ) : 198 (M*+l) . Example 21 ( 5R) - (-) -3 . 3-Dimethyl-5-ethyl-l-pivaloylpyrrolidin-2-one 1221 ( 2 2 ) Reaction of the auxiliary (8) from Example 7 (0.230g, 1.63 mmol) in solution in THF (15 ml) with nBuLi (1.6M, 1.12 ml, 1.79 mmol) and pivaloyl chloride (0.24 ml, 1.95 mmol) furnished the N-acyl derivative (22) as a colourless oil (0.290g, 79%); maχ (CH 2 C1 2 ) : 1729 and 1688 cm "1 ; [α] D 21 = -3.0° (c 0.4, CHC1 3 ) ; (Found: C, 69.29; H, 10.50; N, 6.59. C 13 H 23 N0 2 requires C, 69.29; H, 10.28; N, 6.21%); <5 H (CDC1 3 , 300 MHz): 0.85 (3H, t, J=7.4 Hz), 1.15 (3H, s) , 1.24 (3H, s) , 1.32 (9H, s) , 1.38 (IH, m) , 1.60 (IH, dd, J=7.8 and 12.9 Hz), 1.83 (IH, m) , 2.02 (2H, d, J=7.6 and 12.9 Hz), 4.10 (IH, m) ; m/z (CI + , NH 3 ) : 228, 226 (M * +l) , 142. Example 22 (5R)-(-)-3.3-Dimethyl-5-ethyl-l-(3-phenylpropionyl)- pyrrolidin-2-one (23) ( 23) Reaction of the auxiliary (8) from Example 7 (0.40g, 2.83 mmol) in solution in THF (15 ml) with nBuLi (1.5M, 2.08 ml, 3.12 mmol) and 3-phenylpropionyl chloride (0.51 ml, 3.40 mmol) furnished the N-acyl derivative (23) as a colourless oil (0.659g, 85%); ^ (CH 2 C1 2 ) : 1732 and 1694 cm "1 ; [α] D 21 = -71.2* (c 0.53, CHC1 3 ) ; (Found: C, 74.58; H, 8.41. C 17 H 23 N0 2 requires C, 74.69; H, 8.48); <S H (CDC1 3 , 300 MHz): 0.87 (3H, t, J=7.5 Hz) , 1.17 (3H, s) , 1.26 (3H, s) , 1.41 (IH, m) , 1.65 (IH, dd, J=5.4 and 13.2 Hz) , 2.00 (2H, d, J=8.6 and 13.1 Hz), 2.96 (2H, t, J=7.8 Hz), 3.23 (2H, t, J=7.9 Hz), 4.06 (IH, m) , 7.22 (5H, m) ; m/Z (CI + , NH 3 ) : 274 (M * +l) , 142. Example 23 (5R) - (-) -l-Crotonyl-3 . 3-dimethyl-5-ethylpyrrolidin-2-one 1141 ( 2 4 ) Reaction of the auxiliary (8) from Example 7 (0.425g, 3.01 mmol) in solution in THF (15 ml) with nBuLi (1.6M, 2.07 ml, 3.32 mmol) and crotonyl chloride (0.535 ml, 3.62 mmol) furnished the N-acyl derivative (24) as a colourless oil (0.542g, 86%); maχ (CH 2 C1 2 ) : 1728, 1681, 1637, 1333 and 1348 cm "1 ; [α] 0 23 = -129.6° (c 1.20, CHC1 3 ) ; <S„ (CDC1 3 , 300 MHz): 0.89 (3H, t, J=7.4 Hz), 1.18 (3H, s) , 1.27 (3H, s) , 1.46 (IH, m) , 1.65 (IH, dd, J=5.8 and 13.1 HZ), 2.93 (3H, d, J=6.3 Hz) , 2.02 (IH, dd, J=8.4 and 13.1 Hz), 2.08 (IH, m) , 4.10 (IH, m) , 7.16 (2H, m) ; m/z (CI + , NH 3 ) : 210 (M + +l) , 194, 180, 112, 69. Examples 24-30 General procedure for alkylation of N-acylated auxiliaries The N-acyl derivative was dissolved in THF and cooled to 0°C. A solution of LDA in THF was then added, the mixture was stirred at 0'C for 1 hour and then quenched by addition of the stated electrophile. The mixture was stirred at 0°C for 2 hours and allowed to reach room temperature overnight. The reaction mixture was poured onto saturated aqueous ammonium chloride solution (20 ml) and extracted repeatedly with diethyl ether (4x30 ml) . The combined extracts were washed with brine and dried (MgS0 4 ) . After concentration in vacuo. the residue was purified by flash column chromatography on silica to give the alkylated N-acyl derivative. Example 24 (2'S.5S)-(-)-1-(2'-Benzylpropionyl)-5-t-butyldimethyl- silyloxymethyl-3.3-dimethylpyrrolidin-2-one (25) B u ( 25) Reaction of the N-acyl derivative (10) from Example 9 (0.127g, 0.41 mmol) in THF (2.5 ml) with LDA (0.5M, 1.01 ml, 0.51 mmol) and benzyl bromide (0.145 ml, 0.123 mmol) and purification by flash column chromatography eluting with 40-60 petroleum ether/ethyl acetate (9:1) furnished the alkylated N-acyl derivative (25) as a clear oil (O.llδg, 73%); mχ (thin film): 1693 and 1737 cm '1 ; [α] D 26 ' 5 = -67° (c 1.1, CHC1 3 ) ; δ H (CDC1 3 , 300 MHz): 0.01 (3H, s, SiCH 3 ) , 0.03 (3H, s, SiCH 3 ) , 0.86 (9H, s, C(CH 3 ) 3 ), 1.06 (3H, d, J=6.7 Hz, CHCH 3 ) , 1.21 (3H, s, CCH 3 ) , 1.26 (3H, s, CCH 3 ) , 1.93-1.96 (2H, m, CCH 2 ) , 2.51 (IH, dd, J=9.2 and 13.2 Hz), 3.11 (IH, dd, J=5.5 and 13.2 Hz, aryl CH) , 3.60-3.70 (2H, m) , 4.02-4.08 (IH, m) 4.23-4.28 (IH, m) , 7.16-7.27 (5H, m, aryl); <5 C (CDC1 3 , 50 MHz) : -5.61 (CH 3 ) , 15.37 (CH 3 ) , 18.13 (C) , 25.66 (CH 3 ) , 25.75 (CH 3 ) , 27.31 (CH 3 ) , 34.40 (CH-.) , 40.15 (CH) , 40.83 (CH) , 41.85 (C) , 54.75 (CH) , 62.68 (CH 2 ) , 126.35 (CH) , 128.42 (CH) , 129.47 (CH) , 139.76 (C) , 178.64 (CO) and 181.52 (CO); m/z (CI\ NH 3 ) : 404 (M * +l) . Example 25 (2'S.5R)-(-)-1-(2'-Benzylpropionyl)-3.3.5-trimethyl- pyrrolidin-2-one (26) ( 2 6 ) Reaction of the N-acyl derivative (15) from Example 14 (0.193g, 1.05 mmol) in THF (11 ml) with LDA (0.5M, 1.26 mmol) and benzyl bromide (0.38 ml, 3.15 mmol) furnished the alkylated N-acyl derivative (26) as a colourless oil (0.231g, 80%) with a diastereomeric excess of 96%; v maχ (CH 2 C1 2 ) : 1729 and 1693 cm "1 ; [α] 0 23 = -20° (c 0.6, CHC1 3 ) ; <S H (CDC1 3 , 300 MHz): 1.11 (3H, d, J=6.7 Hz, CH 3 ) , 1.17 (3H, d, J=6.2 Hz, CH 3 ) , 1.21 (3H, s, CH 3 ) , 1.47 (IH, dd, J=7.8 and 13.0 Hz, CH 2 CH) , 2.05 (IH, dd, J=8.5 and 13.0 Hz, CH 2 CH) , 2.60 (IH, dd, J=8.0 and 13.2 Hz, CH 2 Ph) , 3.05 (IH, dd, J=6.9 and 13.2 Hz, CH 2 CH) , 4.1 (IH, m) 4.22 (IH, m) , 7.24 (5H, , aryl); m/z (CI + , NH 3 ) : 274 (M + +l) , 273, 258, 182, 128. Example 26 ( 2 ' R .5S ) - ( -) -1- ( 2 ' -Benzylpropionyl ) -5-t-butyldimethyl- silyloxymethyl-3 . 3-dimethylpyrrolidin-2-one (27 ) ( 2 7 ) Reaction of the N-acyl derivative (12) from Example 11 (0.067, 0.72 mmol) in THF (2 ml) with LDA (0.5M, 0.43 ml, 0.215 mmol) and methyl iodide (0.032 ml, 0.516 mmol) and purification by flash column chromatography eluting with 40-60 petroleum ether/ethyl acetate (9:1) furnished the alkylated N-acyl derivative (27) as a clear oil (0.050g, 72%); i,^ (thin film): 1693 and 1736 cm "1 ; [α] 0 26 ' 5 = -102.5° (c 0.8, CHC1 3 ) ; <S H (CDC1 3 , 300 MHz): 0.02 (3H, S, SiCH 3 ) , 0.04 (3H, s, SiCH 3 ) , 0.87 (9H, S, C(CH 3 ) 3 ), 1.07 (3H, s, CCH 3 ) , 1.16 (3H, d, J=6.8 Hz, CHCH 3 ) , 1.26 (3H, s, CCH 3 ) , 1.84 (IH, dd, J=5.4 and 13.1 Hz, (CH 3 ) 2 CCH 2 ), 1.95 (IH, dd, J=9.1 and 13.1 Hz, (CH 3 ) 2 CCH 2 ), 2.59 and 3.04 (2H, AB of ABX, J=7.0, 7.8 and 13.3 Hz, arylCH 2 ) , 3.63 (IH, dd, J=2.3 and 10.1 Hz, OCH 2 ) , 3.97 (IH, dd, J=4.5 and 10.1 Hz, OCH 2 ) , 4.09-4.19 (2H, m, NCH and COCH) , and 7.17-7.29 (5H, , aryl) ; <5 C (CDC1 3 , 50 MHz): -5.67 (CH 3 ) , 17.08 (CH 3 ) , 18.13 (CH 3 ) , 25.37 (CH 3 ) , 25.74 (CH 3 ) , 27.42 (CH 3 ) , 34.425 (CH 2 ) , 39.42 (CH) , 40.63 (CH) , 41.79 (C) , 54.82 (CH) , 62.61 (CH 2 ) , 126.26 (CH) , 128.42 (CH) , 129.34 (CH) , 139.99 (C) , 178.65 (CO) and 181.59 (CO) ; m/z (CI + , NH 3 ) : 404 (M + +l) . Example 27 (2'R.5R)-(-)-1-(2'-Benzylpropionyl)-3.3.5- trimethylpγrrolidin-2-one (28) ( 28 ) Reaction of the N-acyl derivative (18) from Example 17 (0.317g, 1.22 mmol) in THF (13ml) with LDA (0.5M, 1.46 mmol) and methyl iodide (0.225 ml, 3.67 mmol) furnished the alkylated N-acyl derivative (28) as a colourless oil ( *0.203g**, 62%)' with a diastereomeric excess of 89%; ι/mβx„ (CH 2 C1 2 ) :1692 and 1729 cm '1 ; [α] 0 23 =-76 β (c 0.6, CHC1 3 ) ; δ„ (CDC1 3 , 300 MHz): 1.08 (IH, s, gem -CH 3 ) , 1.15 (3H, d, J=6.9 Hz, CH 3 ) , 1.26 (3H, s, gem -CH 3 ) , 1.36 (3H, d, J=6.3 Hz, CH 3 ) , 1.42 (IH, dd, J=5.2 and 13.0 Hz, CH 2 CH) , 2.01 (IH, dd, J=8.5 and 13.0 Hz, CH 2 CH) , 2.60 (IH, dd, J=8.0 and 13.4 Hz, CH 2 Ph) , 3.06 (IH, dd, J=6.8 and 13.4 Hz, CH 2 Ph) , 4.17 (2H, , CHN + COCH), 7.26 (5H, , aryl); m/z (CI + , NH 3 ) : 274 (M + +l) , 273, 146, 128.2. Example 28 (2'R.5R)-1-(2'-Benzylisovaleryl)-3.3.5- trimethylpyrrolidin-2-one (29) ( 2 9 ) Reaction of the N-acylated derivative (16) from Example 15 (0.222g, 1.05 mmol) in THF (10 ml) with LDA (0.5M, 1.26 mmol) and benzyl bromide (0.19 ml, 3.16 mmol) furnished the alkylated N-acyl derivative (29) as a colourless oil (0.236g, 75%) with a diastereomeric excess of 98%; mχ (CH 2 C1 2 ) :1731 and 1688 cm *1 ; <S H (CDC1 3 , 300 MHz): 0.86 (3H, d, J=5.4 Hz) , 0.98 (3H, d, J=5.4 Hz, CH 3 ) , 1.06 (3H, d, J=5.4 Hz) , 1.07 (3H, s) , 1.1 (3H, s) , 1.29 (IH, dd, J=5.0 and 13.0 Hz), 1.93 (IH, dd, J=8.6 and 13.0 Hz), 2.01 (IH, m) , 2.82 (IH, dd, J=11.3 and 13.2 Hz), 2.97 (IH, dd, J=4.7 and 13.2 Hz), 4.11 (IH, m) , 4.25 (IH, m) , 7.17 (5H, m) ; m/z (CI + , NH 3 ):302 (M * +l) , 258, 128. Example 29 (2'S.5R)-(-)-!-(2'-Benzylpropionyl)-3.3-dimethyl-5- ethylpyrrolidin-2-one (30) ( 30 ) Reaction of the N-acylated derivative (21) from Example 20 (0.194g, 0.98 mmol) in THF (10ml) with LDA (0.5 M, 1.17 mmol) and benzyl bromide (0.35 ml, 2.94 mmol) furnished the alkylated N-acyl derivative (30) as a colourless oil (0.220g, 78%) with a diastereomeric excess of 95%; [α] D 21 =-42.3' (c 0.6, CHC1 3 ) ; (Found: C, 75.16; H, 8.65. C 18 H 25 N0 2 requires C, 75.22; H, 8.77%); <5 H (CDC1 3 , 300 MHz):0.80 (IH, t, J=7.2 Hz), 1.20 (3H, d, J=7 Hz), 1.19 (3H, s) , 1.25 (IH, m) , 1.59 (IH, dd, J=5.8 and 13.4 HZ), 1.87 (IH, m) , 1.99 (IH, dd, J=8.4 and 13.5 Hz), 2.57 (IH, dd, J=8.6 and 13.5 Hz), 3.09 (IH, dd, J=6.0 and 13.4 Hz), 4.07 (2H, m) , 7.23 (5H, m) ; m/z (EI + ):287 (M * ) , 272, 142, 118, 91. Example 30 (2'R.5R)-(-)-!-(2'-Benzylpropionyl)-3,3-dimethyl-5- ethylpyrrolidin-2-one (31) ( 31 ) Reaction of the N-acylated derivative (23) from Example 22 (0.380 g, 1.39 mmol) in THF (14 ml) with LDA (0.5 M, 1.67 mmol) and methyl iodide (0.26 ml, 4.17 mmol) furnished the alkylated N-acyl derivative (31) as a colourless oil (0.110 g, 42%) with a diastereomeric excess of 95%; Vuui (CH 2 C1 2 ) : 1729 and 1692 cm '1 ; [α] D 22 = -86.4* (c 0.9, CHC1 3 ) ; (Found: C, 75.13; H, 9.02; N, 5.12. C 18 H 25 N0 2 requires C, 75.22; H, 8.77; N, 4.87%); <5 H (CDC1 3 , 300 MHz): 0.88 (3H, t, J=7.2 Hz) , 1.08 (3H, S) , 1.15 (3H, d, J=7.3 Hz), 1.26 (3H, s) , 1.46 (IH, ) , 1.62 (IH, dd, J=6.0 and 13.3 Hz), 1.93 (IH, dd, J=8.7 and 13.3 Hz), 2.02 (IH, m) , 2.59 (IH, dd, J=7.7 and 13.0 Hz), 3.06 (IH, dd, J=6.7 and 13.0 Hz), 4.01 (IH, ) , 4.12 (IH, m) , 7.23 (5H, m) ; m/z (CI + , NH 3 ) : 290, 288 (M * +l) , 287, 273, 142. Examples 31-33 General procedure for aldol addition to N-acylated auxiliaries The N-acyl derivative was dissolved in dichloromethane (5 ml) and cooled to 0°C. Diisopropylethylamine (0.16 ml, 0.94 mmol) and Bu-,BOTf (where Tf represents triflate, i.e. trifluoromethanesulphonate) (0.86 ml, 0.86 mmol) were added as a 1M solution in dichloromethane. After 30 minutes at 0°C the resulting solution was cooled to - 78'C and freshly distilled benzaldehyde (0.095 ml, 0.94 mmol) was added. After 30 minutes at -78"C and 1 hour at 0°C the solution was treated with pH 7 buffer (3 ml) and methanol (4 ml) , and to this mixture was slowly added methanol/aqueous hydrogen peroxide (2:1) (3 ml). After 1 hour of stirring the solvents were removed in vacuo and the residue was extracted with diethyl ether (4 x 40 ml) . The combined organic extracts were washed with 5% aqueous sodium bicarbonate solution and brine and then dried (MgS0 4 ) . The solvent was removed and the residue purified by flash column chromatography, eluting with 40-60 petroleum ether/ethyl acetate (4:1) to yield the desired product. Example 31 (2'R.3'R.5R)-(-)-1-(3 '-Hvdroxy-2 '-methyl-3'- phenylpropionyl)-3.3.5-trimethylpyrrolidin-2-one (32) ( 32 ) Reaction of the N-acyl derivative (15) from Example 14 (0.143g, 0.78 mmol) furnished compound (32) with a diastereomeric excess of 98% as an oil (0.189g, 84%) which crystallised on cooling; maχ (CH-,C1 2 ) : 3518, 3054, 2986, 1733, 1674, 1422, 1272 and 1259 cm "1 ; [ ] D 22 =-26.9 ° (c 0.7, CHC1 3 ) ; (Found : C, 70.26; H, 7.92; N, 5.12. C 17 H 23 N0 3 requires C, 70.56; H, 8.01; N, 4.84%) ; 5H (CDCl 3 , 300 MHz): 1.09 (3H, d, J=7.1 Hz) , 1.17 (3H, s) , 1.27 (3H, S) , 1.36 (3H, d, J=6.3 Hz, CH 3 ) , 1.56 (IH, dd, J=5.6 and 13.1 Hz), 2.09 (IH, dd, J=8.4 and 13.1 Hz), 4.11 (IH, m) , 4.26 (IH, m) , 5.16 (IH, dd, J=3.05 Hz) , 7.36 (5H, m) ; m/z (CI + , NH 3 ) : 272 (M * -18) , 184, 128. Example 32 (2 " R.3'R.5R)-(-)-3.3-Dimethyl-5-ethyl-l-(3 '-Hvdroxy-2'- methyl-3'-phenylpropionyl) yrrolidin-2-one (33) ( 33) Reaction of the N-acyl derivative (21) from Example 20 (0.168g, 0.852 mmol) furnished compound (33) with a diastereomeric excess of 98% (0.203g, 79%) ; v (CH 2 C1 2 ) : 3054, 2986, 1734, 1670, 1422, 1272 and 1259 cm *1 ; [α] D 21 =-54.8° (c 0.5, CHC1 3 ) ; (Found : C, 71.25; H, 8.12; N, 4.63. C 18 H 25 N0 3 requires C, 71.26; H, 8.30; N, 4.62%; δ H (CDC1 3 , 300 MHz): 0.89 (3H, t, J=7.7 Hz) , 1.10 (3H, d, J=6.4 HZ), 1.17 (3H, s) , 1.25 (3H, s) , 1.47 (3H, s) , 1.64 (dd, J=6.0 and 13.3 Hz), 1.99 (2H, m) , 4.10 (2H, m) , 5.13 (2H, d, J=3.2 Hz) , 7.33 (5H, m) ; m/z (CI + , NH 3 ) : 302 (M*-l) , 286, 198, 142, 112. Example 33 ( 1"R . 2 ' R . 5R) - (-) -1- ( 2 ' - ( l"-hvdroxy-l"- phenylmethyl)butyryl)-3.3.5-trimethylpyrrolidin-2-one (34) ( 34) Reaction of the N-acyl derivative (19) from Example 18 (0.307g, 1.56 mmol) furnished compound (34) with a diastereomeric excess of 98% (0.387g, 86%); [α] 0 21 =-47* (σ 0.5, CHC1 3 ) ; (Found : C, 71.17; H, 8.53; N, 4.38. C 18 H 25 N0 3 requires C, 71.26; H, 8.30; N, 4.62%; <$ H (CDC1 3 , 300 MHZ): 0.82 (3H, t, J=7.5 Hz) , 1.09 (3H, s) , 1.27 (3H, s) , 1.37 (3H, d, J=6.2 Hz) , 1.53 (IH, dd, J=5.8 and 13.0 Hz), 1.63 (IH, m) , 1.83 (IH, m) , 2.01 (IH, dd, J=8.4 and 13.0 HZ), 4.20 (IH, m) , 4.16 (IH, m) , 5.03 (IH, d, J=4.5 Hz), 7.39 (5H, m) ; m/z (CI\ NH 3 ) : 302 (M*- 1) , 286, 198, 128. Example 34 Preparation of polymer attached auxiliary ______ (5S)-3.3-Dimethyl-l-p-Methoxybenzyl-5-p- methoxγbenzyloxymethylpyrrolidin-2-one (35) A solution of auxiliary (4) from Example 3 in THF/DMF (1:1) (20ml) was stirred with sodium hydride (0.26g, 10.8 mmol) to form a creamy white solution; extensive bubbling was initially observed. After three hours p- methoxybenzyl chloride (0.58 ml, 4.28 mmol) was added and the resulting solution was stirred for 24 hours. The THF was removed under reduced pressure and the DMF solution was poured into water and extracted with diethyl ether. The combined extracts were dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. A crude 1 H NMR indicated the correct product. Chromatography on silica, eluting with 40-60 petroleum ether followed by 40-60 petroleum ether/ethyl acetate (1:1) gave the product (35) as a yellow oil (0.670g, 81.4%). <S H (CDC1 3 ) : 7.22, 6.89 (4H, d, AB system, J AB =8.58 Hz, aryl), 7.09, 6.80 (4H, d, AB system, J AB =8.66 Hz, aryl), 4.89, 3.98 (2H, d, AB system, J=1 .69 Hz, NCH 2 Ph) , 4.38 (2H, s, OCH 2 Ph) , 3.82 (3H, s, 0CH 3 ) , 3.78 (3H, s, OCH 3 ) , 3.6-3.4 (3H, m, ABX system, NCHCH 2 0) , 1.87, 1.64 (2H, dd, ABX system, J ftB =7.45 Hz, J Aχ =12.76 Hz, (CH 3 ) 2 CH 2 ), 1.23 (3H, s, gem-CH 3 ) , 1.11 (3H, s, gem-CH 3 ) ; δ_ (CDC1 3 ) 180.46 (CO), 159.58 (para-Ph) , 159.06 (para-Ph) , 130.05 (ipso-Ph), 129.50 (ortho-Ph) , 113.93 (meta-Ph) , 72.88 (OCH 2 Ph) , 71.14 (CHCH 2 0) , 55.15 (OCH 3 on O aralkylated) , 53.50 (0CH 3 on N aralkylated), 53.33 (NCHCH 2 ) , 44.05 (NCH 2 Ph) , 39.97 ( (CH 3 ) 2 CCH 2 ) , 37.17 ( (CH 3 ) 2 CCH 2 ) , 25.41 (gem-CH 3 ) , 25.18 (gem-CH 3 ) . ii (5S)-3.3-Dimethyl-5-hvdroxymethyl-l-p- methoxybenzylpyrrolidin-2-one (36) H ( 36) A solution of product (35) from (i) above (l.294g, 3.37 mmol) in dichloromethane (20 ml) was treated with 2,3- dichloro-5,6-dicyano-l,4-benzoquinone (l.lg, 4.85 mmol) and water (1 ml) and the resulting solution was stirred overnight. Saturated aqueous sodium bicarbonate was added and the organic phase was separated. The aqueous phase was extracted with dichloromethane and ethyl acetate. The solvents were removed from the combined organic phases and the residue was dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous soldium chloride, dried (Mg S0 4 ) and the solvent was removed under reduced pressure. Crude 1 H NMR indicated the presence of product (36) and p- anisaldehyde. Chromatography on silica eluting with 40- 60 petroleum ether/ethyl acetate (7:3) yielded the aldehyde, further elution with ethyl acetate yielding product (36) .(0.8802 ' g, 99%) as a white crystalline material; (Found: C, 68.42; H, 8.30; N, 5.36. C 15 H 21 N0 3 requires C, 68.42; H, 8.04; N, 5.32%) ; «5 H (CDC1 3 ) : 7.18, 6.85 (4H, d, AB system, J AB = 8.64 Hz, aryl) , 4.75, 4.20 (2H, d, AB system, J=14.88 Hz, NCH 2 Ph) , 3.79 (3H, S, OCH 3 ) , 3.74 (IH, m, ABX system, NCHCH 2 ) , 3.6-3.48 (2H, m, ABX system, NCHCH 2 0) , 1.83, 1.81 (2H, dd, AB system, J AB = 7.45 Hz, (CH 3 ) 2 CCH 2 ) , 1.25 (3H, s, gem-CH 3 ) , 1.14 (3H, S, gem-CH 3 ) ; <S C (CDC1 3 ) : 181.26(CO) , 159.24 (para-Ph) , 129.36 (ortho-Ph) , 129.25 (ipso-Ph) , 114.26 (meta-Ph) , 62.22 (CHCH 2 0) , 55.37 (OCH 3 on N-aralkylated) , 55.19 (NCHCH 2 ) , 44.09 (NCH-,Ph) , 40.16 ( ( CH 3 ) 2 CCH 2 ) , 36.19 ((CH 3 ) 2 CCH 2 ) , 25.30 (gem-CH 3 ) . iii Polvmer-attached (5S)-3.3-dimethyl-5-hvdroxymethyl- pyrrolidin-2-one (37) 0 . Pol y me r ( 37 ) A solution of product (36) from (ii) above (0.7719g, 2.931 mmol) in THF/DMF (1:1) (20 ml) was treated with sodium hydride (0.14g, 5.75 mmol) for 4 hours, whereafter 0.5016g of 75% chlorinated Merrifield's resin (2.43 mmol Cl) was added and the reaction mixture was stirred for 48 hours. The product was filtered, washed successively with methanol, water, THF and methanol and dried under reduced pressure. Infrared spectroscopy of the polymer indicated a new carbonyl frequency at 1685 cm *1 and disappearance of the stretching frequency at 1265 cm "1 characteristic of Merrifield's resin. Unreacted starting material (36) (0.143g) was recovered from the combined organic washing phases by solvent removal and extraction of the residue with ethyl acetate, the amount of recovered material confirming that complete incorporation of auxiliary into the polymer had occurred. The polymer-attached N-protected auxiliary was N- deprotected by stirring the polymer in toluene/water (15:1) with an excess of cerium (IV) ammonium nitrate for 36 hours. The resulting polymer was filtered, washed successively with methanol, water, THF and methanol and dried under reduced pressure. 1 H NMR of the washings indicated only the presence of p-anisaldehyde. Infrared spectroscopy of the polymer product (37) showed a carbonyl frequency at 1698 cm *1 . Example 35 N-acylation of polvmer-attached auxiliary (37) Polymer-attached (5S)-3,3-dimethyl-5-hydroxymethyl- pyrrolidin-2-one (37) (approx. 2.4 mmol NH) from Example 34 (iii) was swelled in THF (40 ml) and treated with a solution of LDA in THF (2M, 1.44 ml) at 0°C for 1 hour, followed by addition of 3-phenylpropionyl chloride (0.43 ml, 2.89 mmol). The reaction mixture was stirred at 0°C for 2 hours and then quenched with methanol. The resin was filtered, washed successively with methanol, water, THF and methanol and dried under reduced pressure. Infrared spectroscopy of the resin showed two carbonyl stretching frequencies at 1734 and 1696 cm '1 , indicating that the polymer-attached auxiliary (37) had been N- acylated to form product (38) 0. Pol y me r ( 38) Examples 36-45 General procedure for cleavage N-acylated auxiliary was dissolved in THF/water (3:1) (10 ml/mmol) and cooled to O'C. Solid lithium hydroxide (2.3 equivalents) was then added and the mixture was stirred at O'C for 1 hour and then warmed to room temperature, monitoring by thin layer chromatography to determine completion of the cleavage reaction. Aqueous sodium bicarbonate was added to the resulting mixture, which was then extracted with diethyl ether. The combined organic extracts were washed with brine, dried (MgS0 4 ) and subjected to solvent evaporation to yield N- unsubstituted auxiliary as a white solid. The aqueous phase was acidified to pH 2 by addition of 2M hydrochloric acid and extracted with ethyl acetate (3 times) to yield the acid corresponding to the N-acyl substituent of the starting material. The following results were obtained: In general no traces of endocyclic products resulting from cleavage of the pyrrolidinone ring were observed. In Example 44 NMR(300 MHz) studies indicated that no epimerisation occured. In Examples 40, 41 and 42 NMR(500 MHz) studies using a chiral shift reagent (R,R) l,2-diamino-l,2-diphenylethane indicated that no significant epimerisation of the newly-generated stereogenic centre occured.

Claims: CLAIMS 1. A compound of general formula (I) (where the two R groups are identical lower alkyl groups or together form a lower alkylene group, R 1 represents an organic group and the asterisk denotes that R 1 is predominantly in the R- or S- configuration such that the compound (I) is in substantially enantiomerically pure form, and R 2 represents a hydrogen atom or an acyl group containing a prochiral centre) . 2. A compound as claimed in claim 1 comprising at least 95% of a single enantiomer. 3. A compound as claimed in claim 1 or claim 2 wherein the two R groups are methyl groups. 4. A compound as claimed in any of the preceding claims wherein R 1 represents a group selected from optionally substituted C^^ alkyl, C 2 . 10 alkenyl, C 3 . 10 cycloalkyl-C 1 . 4 alkyl and C 6 . 12 aryl-C^ alkyl groups. 5. A compound as claimed in claim 4 wherein R 1 represents a methyl or ethyl group. 6. A compound as claimed in any of claims 1 to 3 wherein R 1 represents a group of formula CH 2 OP (where P represents an organic group) . 7. A compound as claimed in claim 6 wherein P represents a hydroxyl protecting group or a polymeric group. 8. A compound as claimed in claim 7 in which P represents an insoluble polymer support system. 9. A compound as claimed in any of the preceding claims wherein R 2 represents a hydrogen atom. 10. A compound as claimed in any of claims 1 to 8 wherein R 2 represents an acyl group of formula - CO.R 2a (where R 2a represents a C 10 alkyl, C 2 . 10 alkenyl, C 6 . 10 aryl - C,. 4 alkyl or C 6 . 20 aryl group) . 11. A compound as claimed in claim 10 wherein R 2 represents propionyl, butyryl, crotonyl, isovaleryl, pivaloyl or 3-phenylpropionyl. 12. The compounds: (5R)- and (5S)-3,3-dimethyl-5-hydroxymethylpyrrolidin-2- one and O-protected derivatives thereof; (5R)- and (5S)-3,3,5-trimethylpyrrolidin-2-one; and (5R)- and (5S)-3,3-dimethyl-5-ethylpyrrolidin-2-one. 13. A process for the preparation of a compound of general formula (I) as defined in claim 1 which comprises (i) cyclising a compound of general formula (VI) COOR 5 H 2 N . CH . CH 2 . CH 2 . COOH (VI ) (where R 5 represents a carboxyl protecting group and the meaning of the asterisk is as defined in claim 1) to yield a compound of general formula (VII) (where R 5 and the asterisk are as defined above) ; (ii) reducing said compound (VII) to a corresponding 5R- or 5S- hydroxymethyl derivative; (iii) reacting said derivative with 2-methoxypropene to yield a compound of general formula (VIII) 0 (where the meaning of the asterisk is as defined above) ; (iv) alkylating and deprotecting said compound (VIII) to yield a compound of general formula (I) in which R 1 represents a hydroxymethyl group and R 2 represents a hydrogen atom; (v) if necessary or desired reacting said compound (I) so as to generate a desired R 1 grouping; and (vi) if necessary or desired reacting a compound (I) in which R 2 represents a hydrogen atom with an acylating agent serving to introduce a desired acyl group R 2 . 14. Use of compounds of general formula (I) as defined in any of claims 1 to 12 in stereoselective syntheses. 15. Use as claimed in claim 14 wherein a compound of general formula (I) in which R 2 represents an acyl group containing a prochiral centre is subjected to one or more stereoselective reactions involving said prochiral centre, and the resulting modified acyl group is cleaved and a compound of general formula (I) in which R 2 represents a hydrogen atom is generated. 16. Use as claimed in claim 15 wherein the modified acyl group is cleaved by acid or base catalysed hydrolysis. 17. Use as claimed in claim 15 or claim 16 wherein the group R 2 contains an α-methylene group and is subjected to stereoselective reaction with an electrophile. 18. Use as claimed in claim 15 or claim 16 wherein the group R 2 is a 2-alkenoyl group and is subjected to stereoselective Michael addition by reaction with a nucleophile. 19. Use as claimed in claim 15 or claim 16 wherein the group R 2 is a 2-alkenoyl group and is subjected to stereoselective Diels-Alder reaction with a conjugated diene. 20. Use as claimed in claim 15 or claim 16 wherein the group R 2 has a hydrogen atom α to the carbonyl group and is subjected to stereoselective aldol condensation with an aldehyde.

Inventors: DAVIES STEPHEN GRAHAM, POLYWKA MARIO EUGENIO COSAMINO, DAVIES, STEPHEN, GRAHAM, POLYWKA, MARIO, EUGENIO, COSAMINO
Applicants: DAVIES STEPHEN GRAHAM, OXFORD ASYMMETRY LTD, POLYWKA MARIO EUGENIO COSAMINO, DAVIES, STEPHEN, GRAHAM, OXFORD ASYMMETRY LIMITED, POLYWKA, MARIO, EUGENIO, COSAMINO
Application year: 1994
Main classification: C07D207
IPC codes: C07B53, C07D207, C07F7, C08F8